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奥卡西平刻痕片仿制药与原研药溶出行为及相关指标的一致性评价研究
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篇名: 奥卡西平刻痕片仿制药与原研药溶出行为及相关指标的一致性评价研究
TITLE: Consistency Evaluation on the Dissolution Behavior and Related Indicators between Generic and Original Pre- parations of Oxcarbazepine Scored Tablets
摘要: 目的:评价奥卡西平刻痕片仿制药与原研药溶出行为的一致性,并比较两者的外观、半片制剂的脆碎度及分割质量损失以及不同企业原料药的晶型、晶体形貌。方法:采用高效液相色谱法测定含量;采用桨法(设置转速60r/min,温度37.0℃)测定仿制药与原研药在4种不同溶出介质[含0.6%十二烷基硫酸钠的盐酸溶液(pH=1.2)、含0.6%十二烷基硫酸钠的醋酸盐缓冲溶液(pH=4.5)、含0.6%十二烷基硫酸钠的磷酸盐缓冲溶液(pH=6.8)、含0.6%十二烷基硫酸钠的水溶液]中的累积溶出度,采用相似因子法评价两者溶出曲线的相似性,并评价半片与整片制剂的批内均一性;采用脆碎度检测仪及电子天平测定半片制剂的脆碎度及分割质量损失;采用X射线衍射仪及扫描电子显微镜观察不同企业原料药的晶型和晶体形貌。结果:奥卡西平检测质量浓度的线性范围为33.42~401.09μg/mL(r=0.9999);定量限为0.10μg/mL,检测限为0.04μg/mL;精密度、稳定性、重复性、耐用性试验的RSD均小于2%;回收率为99.80%~101.63%(RSD为0.37%~0.91%,n=3)。仿制药A、B和原研药在4种不同溶出介质中90min时的平均累积溶出度分别为92%、87%、90%[含0.6%十二烷基硫酸钠的盐酸溶液(pH=1.2)];94%、94%、90%[含0.6%十二烷基硫酸钠的醋酸盐缓冲溶液(pH=4.5)];95%、95%、91%[含0.6%十二烷基硫酸钠的磷酸盐缓冲溶液(pH=6.8)];97%、98%、95%(含0.6%十二烷基硫酸钠的水溶液)。仿制药A、B和原研药在上述4种溶出介质中的相似因子分别为66、81,71、69,71、61,59、39。前15min时,仿制药A、B和原研药半片与整片的溶出度差值分别为-3%~13%、-2%~24%、-3%~7%;仿制药A半片、整片累积溶出度的RSD分别为6%~14%、2%~9%(n=12),仿制药B为4%~10%、1%~8%(n=12),原研药为2%~7%、2%~8%(n=12)。原研药外观为梭形,刻痕较深;仿制药片形各异,且刻痕明显浅于原研药。仿制药A、B和原研药的脆碎度、分割质量损失分别为0.62%、0.67%,0.12%、0.11%,0.08%、0.05%。国产原料药呈不规则的块状和碎屑,原研药企业产原料药呈规则的扁平长方体和规则的条状且碎屑少;但两者的X射线衍射特征峰基本一致。结论:仿制药A在4种溶出介质中的溶出行为与原研药一致;仿制药B在含0.6%十二烷基硫酸钠的水溶液中的溶出行为与原研药不同;原研药掰分前后批内均一性无明显变化,而仿制药A、B掰分后的批内均一性较整片有所降低;仿制药的脆碎度和分割质量损失均高于原研药;两者原料药晶型相同但晶体形貌存有差异。
ABSTRACT: OBJECTIVE:To evaluate the dissolution behavior consistency between the generic drugs and original drugs of Oxcarbazepine scored tablets ,and to compare the appearance ,the friability of the split portions ,loss of mass of the split portions as well as crystal form and morphology of raw material from different enterprises. METHODS :HPLC method was adopted. The paddle method (rotation speed of 60 r/min,the temperature of 37.0℃)was adopted to determine accumulative dissolution rate of generic and original drugs in 4 mediums [ 0.6% SDS hydrochloric acid solution (pH=1.2),0.6% SDS acetate buffer solution (pH=4.5),0.6% SDS phosphate buffer solution (pH=6.8)and 0.6% SDS water solution]. The similarity factor method was used to evaluate the similarity of dissolution curves as well as intra-batch uniformity of the split portions and whole tablets. The friability tester and electronic balance were used to determine the friability and the loss of mass of the split portions. X-ray diffractometer and scanning electron microscope were used to observe the crystal form and crystal morpho logy of the raw materials of different enterprises. RESULTS :The linear range of oxcarbazepine was LOD was 0.04 μg/mL;RSDs of precision ,stability,reprodu- cibility and durability tests were lower than 2.0%;the reco- veries were 99.80%-101.63%(RSD=0.37%-0.91%,n=3). The average cumulati ve dissolution rate of generic drug A , generic drug B and original drug in 4 different dissolution media at 90 min were 92%,87%,90% [0.6% SDS hydrochloric acid solution(pH=1.2)];94%,94%,90% [0.6% SDS acetate buffer solution (pH=4.5)];95%,95%,91% [0.6% SDS phosphate buffer solution (pH 6.8)];97%,98%,95%(0.6% SDS water solution ). The similarity factors of generic drug A ,generic drug B and original drug in 4 kinds of different dissolution media were 66 and 81,71 and 69,71 and 61,59 and 39. In the first 15 min,the difference of dissolution rate of split portions and whole tablets were -3%-13%,-2%-24% and -3%-7% for generic drug A , generic drug B and original drug ,respectively. RSDs of accumulative dissolution rate of split portions and whole tablets were 6%-14% and 2%-9% for generic drug A (n=12),4%-10% and 1%-8% for generic drug B (n=12)and 2%-7% and 2%-8% for original drug. The appearance of the original drug was fusiform ,and the notch was deep ;the shape of the generic drug was different from each other ,and the notch of the generic drug was significantly shallower than that of original drug. The friability , the loss of mass of the split portions for generic drug A and generic drug B ,original drug were 0.62%and 0.67%,0.12% and 0.11%,0.08% and 0.05%. The domestic raw materials possessed irregular lumps and debris ,while the raw materials produced by original drug enterprises possessed regular flat cuboids and regular strips with little debris ;but X-ray diffraction peaks of them were basically the same. CONCLUSIONS :The dissolution behavior of generic drug A in 4 medium is consistent with that of the original drug;dissolution behavior of generic drug B in water containing 0.6%SDS is different from that of the original drug ;there is no significant change in the homogeneity of the original drug before and after splitting ,but the homogeneity of the generic drug A and B after splitting is lower than that of the whole tablet ;the fragility of generic drugs and loss of mass of split portions are higher than those of the original drugs ;two kinds of raw material have the same crystal form but different crystal morphology.
期刊: 2020年第31卷第12期
编辑: 吕蓓蓓,杨海源,程华,魏文芝,张敏娟
AUTHORS: LYU Beibei ,YANG Haiyuan ,CHENG Hua,WEI Wenzhi ,ZHANG Minjuan
关键字: 奥卡西平;溶出行为;刻痕片;仿制药;原研药;一致性评价;高效液相色谱法
KEYWORDS: Oxcarbazepine;Dissolution behavior ;Scored tablets ;Generic drug ;Original drug ;Consistency evaluation ;HPLC
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